Hematology Drugs in the Pipeline
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For Acute Myeloid Leukemia
Published OnlineFirst September 21, 2010; DOI: 10.1158/1078-0432.CCR-10-0382 Published OnlineFirst on September 21, 2010 as 10.1158/1078-0432.CCR-10-0382 Clinical Therapy Clinical Cancer Research Sequential Cytarabine and α-Particle Immunotherapy with Bismuth-213–Lintuzumab (HuM195) for Acute Myeloid Leukemia Todd L. Rosenblat1, Michael R. McDevitt1, Deborah A. Mulford1, Neeta Pandit-Taskar1, Chaitanya R. Divgi1, Katherine S. Panageas1, Mark L. Heaney1, Suzanne Chanel1, Alfred Morgenstern2, George Sgouros1, Steven M. Larson1, David A. Scheinberg1, and Joseph G. Jurcic1 Abstract Purpose: Lintuzumab (HuM195), a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest single-agent activity against acute myeloid leukemia (AML). To increase the potency of the antibody without the nonspecific cytotoxicity associated with β-emitters, the α-particle–emitting ra- dionuclide bismuth-213 (213Bi) was conjugated to lintuzumab. This phase I/II trial was conducted to determine the maximum tolerated dose (MTD) and antileukemic effects of 213Bi-lintuzumab, the first targeted α-emitter, after partially cytoreductive chemotherapy. Experimental Design: Thirty-one patients with newly diagnosed (n = 13) or relapsed/refractory (n = 18) AML (median age, 67 years; range, 37-80) were treated with cytarabine (200 mg/m2/d) for 5 days followed by 213Bi-lintuzumab (18.5-46.25 MBq/kg). Results: The MTD of 213Bi-lintuzumab was 37 MB/kg; myelosuppression lasting >35 days was dose limiting. Extramedullary toxicities were primarily limited to grade ≤2 events, including infusion-related reactions. Transient grade 3/4 liver function abnormalities were seen in five patients (16%). Treatment- related deaths occurred in 2 of 21 (10%) patients who received the MTD. -
CD74 Targeted Nanoparticles As Dexamethasone Delivery System for B Lymphoid Malignancies
CD74 targeted nanoparticles as Dexamethasone Delivery System for B lymphoid malignancies DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Georgia Triantafillou, MPH Integrated Biomedical Sciences Graduate Program The Ohio State University 2011 Dissertation Committee John C. Byrd, MD, advisor Natarajan Muthusamy, PhD co-advisor Robert J.Lee, PhD, co-advisor Mitch A.Phelps, PhD, co-advisor Guido Marcucci, MD committee member Susheela Tridandapani, PhD committee member Copyright page Georgia Triantafillou 2011 ABSTRACT Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia and is not curable with standard therapy. In CLL the B lymphocytes appear morphologically mature but immunologically express less mature B cell makers. Specifically, the CLL B cells co-express surface antigens including CD19, CD20, CD5, CD23. Due to nonspecific delivery of the drugs to malignant as well as normal cells, patients experience numerous side effects. Targeted drug delivery to cancer cells is a desirable goal for all anti cancer strategies. Corticosteroids have been proven to be a beneficial and well established part of CLL treatment. Dexamethasone(DEX) is frequently used in CLL therapies as well as other malignancies and antiinflammatory diseases. However, DEX nonspecifically enters all tissues inducing various toxicities to patients. Therefore, DEX treatment is often discontinued or not administered to certain patients. We aimed to deliver this efficient clinical agent via a targeted delivery vehicle and examine its effect on its target B-CLL cells. The main scope of the work presented is the creation of a sterically stable nanoparticle, an ii immunoliposome (ILP), that has DEX encapsulated in its interior and a monoclonal antibody(Mab) in its exterior targeting CLL B cells expressing the surface antigen that is recognized by the Mab. -
Predictive QSAR Tools to Aid in Early Process Development of Monoclonal Antibodies
Predictive QSAR tools to aid in early process development of monoclonal antibodies John Micael Andreas Karlberg Published work submitted to Newcastle University for the degree of Doctor of Philosophy in the School of Engineering November 2019 Abstract Monoclonal antibodies (mAbs) have become one of the fastest growing markets for diagnostic and therapeutic treatments over the last 30 years with a global sales revenue around $89 billion reported in 2017. A popular framework widely used in pharmaceutical industries for designing manufacturing processes for mAbs is Quality by Design (QbD) due to providing a structured and systematic approach in investigation and screening process parameters that might influence the product quality. However, due to the large number of product quality attributes (CQAs) and process parameters that exist in an mAb process platform, extensive investigation is needed to characterise their impact on the product quality which makes the process development costly and time consuming. There is thus an urgent need for methods and tools that can be used for early risk-based selection of critical product properties and process factors to reduce the number of potential factors that have to be investigated, thereby aiding in speeding up the process development and reduce costs. In this study, a framework for predictive model development based on Quantitative Structure- Activity Relationship (QSAR) modelling was developed to link structural features and properties of mAbs to Hydrophobic Interaction Chromatography (HIC) retention times and expressed mAb yield from HEK cells. Model development was based on a structured approach for incremental model refinement and evaluation that aided in increasing model performance until becoming acceptable in accordance to the OECD guidelines for QSAR models. -
Research in Your Backyard Developing Cures, Creating Jobs
Research in Your Backyard Developing Cures, Creating Jobs PHARMACEUTICAL CLINICAL TRIALS IN ILLINOIS Dots show locations of clinical trials in the state. Executive Summary This report shows that biopharmaceutical research com- Quite often, biopharmaceutical companies hire local panies continue to be vitally important to the economy research institutions to conduct the tests and in Illinois, and patient health in Illinois, despite the recession. they help to bolster local economies in communities all over the state, including Chicago, Decatur, Joliet, Peoria, At a time when the state still faces significant economic Quincy, Rock Island, Rockford and Springfield. challenges, biopharmaceutical research companies are conducting or have conducted more than 4,300 clinical For patients, the trials offer another potential therapeutic trials of new medicines in collaboration with the state’s option. Clinical tests may provide a new avenue of care for clinical research centers, university medical schools and some chronic disease sufferers who are still searching for hospitals. Of the more than 4,300 clinical trials, 2,334 the medicines that are best for them. More than 470 of the target or have targeted the nation’s six most debilitating trials underway in Illinois are still recruiting patients. chronic diseases—asthma, cancer, diabetes, heart dis- ease, mental illnesses and stroke. Participants in clinical trials can: What are Clinical Trials? • Play an active role in their health care. • Gain access to new research treatments before they In the development of new medicines, clinical trials are are widely available. conducted to prove therapeutic safety and effectiveness and compile the evidence needed for the Food and Drug • Obtain expert medical care at leading health care Administration to approve treatments. -
Advances in Anticancer Antibody-Drug Conjugates and Immunotoxins
Send Orders for Reprints to [email protected] Recent Patents on Anti-Cancer Drug Discovery, 2014, 9, 35-65 35 Advances in Anticancer Antibody-Drug Conjugates and Immunotoxins Franco Dosio1,*, Barbara Stella1, Sofia Cerioni1, Daniela Gastaldi2 and Silvia Arpicco1 1Dipartimento di Scienza e Tecnologia del Farmaco, University of Torino, Torino, I-10125, Italy; 2Dipartimento di Bio- tecnologie Molecolari e Scienze per la Salute, University of Torino, Torino, I-10125, Italy Received: December 13, 2012; Accepted: February 21, 2013; Revised: March 7, 2013 Abstract: Antibody-delivered drugs and toxins are poised to become important classes of cancer therapeutics. These bio- pharmaceuticals have potential in this field, as they can selectively direct highly potent cytotoxic agents to cancer cells that present tumor-associated surface markers, thereby minimizing systemic toxicity. The activity of some conjugates is of particular interest receiving increasing attention, thanks to very promising clinical trial results in hematologic cancers. Over twenty antibody-drug conjugates and eight immunotoxins in clinical trials as well as some recently approved drugs, support the maturity of this approach. This review focuses on recent advances in the development of these two classes of biopharmaceuticals: conventional toxins and anticancer drugs, together with their mechanisms of action. The processes of conjugation and purification, as reported in the literature and in several patents, are discussed and the most relevant results in clinical trials are listed. Innovative technologies and preliminary results on novel drugs and toxins, as reported in the literature and in recently-published patents (up to February 2013) are lastly examined. Keywords: Antibody drug conjugate, anticancer agents, auristatins immunotoxin, calicheamicins, cross-linkers, duocarmycins, maytansinoids. -
Classification Decisions Taken by the Harmonized System Committee from the 47Th to 60Th Sessions (2011
CLASSIFICATION DECISIONS TAKEN BY THE HARMONIZED SYSTEM COMMITTEE FROM THE 47TH TO 60TH SESSIONS (2011 - 2018) WORLD CUSTOMS ORGANIZATION Rue du Marché 30 B-1210 Brussels Belgium November 2011 Copyright © 2011 World Customs Organization. All rights reserved. Requests and inquiries concerning translation, reproduction and adaptation rights should be addressed to [email protected]. D/2011/0448/25 The following list contains the classification decisions (other than those subject to a reservation) taken by the Harmonized System Committee ( 47th Session – March 2011) on specific products, together with their related Harmonized System code numbers and, in certain cases, the classification rationale. Advice Parties seeking to import or export merchandise covered by a decision are advised to verify the implementation of the decision by the importing or exporting country, as the case may be. HS codes Classification No Product description Classification considered rationale 1. Preparation, in the form of a powder, consisting of 92 % sugar, 6 % 2106.90 GRIs 1 and 6 black currant powder, anticaking agent, citric acid and black currant flavouring, put up for retail sale in 32-gram sachets, intended to be consumed as a beverage after mixing with hot water. 2. Vanutide cridificar (INN List 100). 3002.20 3. Certain INN products. Chapters 28, 29 (See “INN List 101” at the end of this publication.) and 30 4. Certain INN products. Chapters 13, 29 (See “INN List 102” at the end of this publication.) and 30 5. Certain INN products. Chapters 28, 29, (See “INN List 103” at the end of this publication.) 30, 35 and 39 6. Re-classification of INN products. -
Tanibirumab (CUI C3490677) Add to Cart
5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor -
Bendamustine in Patients with Relapsed Chronic Lymphocytic Leukaemia
research paper Randomized phase 2 study of otlertuzumab and bendamustine versus bendamustine in patients with relapsed chronic lymphocytic leukaemia Tadeusz Robak,1 Andrzej Hellmann,2 Summary Janusz Kloczko,3 Javier Loscertales,4 Otlertuzumab (TRU-016) is a humanized anti-CD37 protein therapeutic Ewa Lech-Maranda,5,6 John M. Pagel,7 Anthony Mato,8 John C. Byrd,9 Farrukh that triggers direct caspase-independent apoptosis of malignant B cells and T. Awan,9 Holger Hebart,10 Jose A. induces antibody-dependent cell-mediated cytotoxicity. Patients with Garcia-Marco,11 Brian T. Hill,12 Michael relapsed chronic lymphocytic leukaemia (CLL) received either otlertuzumab Hallek,13,14 Amy J. Eisenfeld,15 Scott C. (20 mg/kg) weekly by IV infusion for two 28-day cycles then every 14 days Stromatt15 and Ulrich Jaeger14,16 for four 28-day cycles and IV bendamustine (70 mg/m2) on Days 1 and 2 1Department of Haematology, Medical University of each cycle for up to six 28-day cycles or bendamustine alone. Thirty-two of Lodz and Copernicus Memorial Hospital, patients were treated with otlertuzumab and bendamustine and 33 with 2 Lodz, Department of Hematology, Medical bendamustine alone. Overall response rate according to the International 3 University of Gdansk, Gdansk, Department of Workshop on Chronic Lymphocytic Leukaemia criteria was 69% in the Haematology, Medical University of Bialystok, otlertuzumab and bendamustine arm and 39% in the bendamustine alone Bialystok, Poland, 4Haematology, Hospital arm (P = 0Á025). Median progression-free survival (PFS) was 15Á9 months Universitario La Princesa, IIS-IP Madrid, Spain, Á 5 in the otlertuzumab and bendamustine arm and 10 2 months in the ben- Department of Haematology, Institute of Haema- = Á tology and Transfusion Medicine, Warsaw, damustine alone arm (P 0 0192). -
Antibody Drug Conjugates in Lymphoma
Review: Clinical Trial Outcomes Nathwani & Chen Antibody drug conjugates in lymphoma 6 Review: Clinical Trial Outcomes Antibody drug conjugates in lymphoma Clin. Investig. (Lond.) Antibody drug conjugates (ADCs) are comprised of monoclonal antibodies physically Nitya Nathwani1 & Robert linked to cytotoxic molecules. They expressly target cancer cells by delivering cytotoxic Chen*,1 agents to cells displaying specific antigens, and minimize damage to normal tissue. The 1Department of Hematology & Hematopoietic Cell Transplantation, City efficacy and tolerability of these agents are primarily determined by the target antigen, of Hope, Duarte, CA, USA the cytotoxic agent and the linker connecting the cytotoxic agent to the monoclonal *Author for correspondence: antibody. Following advances in technology, clinical trials have demonstrated greater Tel.: +626 256 4673 (ext. 65298) efficacy for ADCs compared with the corresponding naked monoclonal antibodies. Fax: +626 301 8116 This review summarizes the features of current clinically active ADCs in lymphoma and [email protected] emphasizes recent clinical data elucidating the benefit of antibody-directed delivery of cytotoxic agents to tumor cells. Keywords: antibody drug conjugates • lymphoma • monoclonal antibodies Lymphoma is the most common hematologic concentration and poor performance status malignancy, and is subdivided into two main are adverse prognostic factors. SEER (Sur- types: Hodgkin lymphoma (HL) and non- veillance, Epidemiology and End Results) Hodgkin lymphoma (NHL). In the United data from the National Cancer Institute, States, there are an estimated 731,277 people 2013 has revealed a significant improvement 10.4155/CLI.14.73 living with or in remission from lymphoma. in survival rates in this group of diseases in In 2013, there were an estimated 79,030 new the last four decades. -
Guide to Treatment Role of Antibodies in Acute Leukemia: Focus on Transplant-Eligible Populations
PRACTICE AID Guide to Treatment Role of Antibodies in Acute Leukemia: Focus on Transplant-Eligible Populations Acute Myeloid Leukemia DRUG STATUS TARGET DOSE EU EMA approved: In combination with daunorubicin and Induction: 3 mg/m2 (up to 5 mg/m2 in EU and 4.5 mg/m2 in US) cytarabine for pts aged ≥15 y with previously untreated, on d 1, 4, and 7 in combination with daunorubicin and cytarabine de novo CD33+ AML, except APL CD33 Consolidation: 3 mg/m2 (up to 5 mg/m2 in EU and 4.5 mg/m2 in US) Gemtuzumab US FDA approved: Newly diagnosed CD33+ AML in adults and 1,2 on d 1 in combination with daunorubicin and cytarabine ozogamicin pediatric pts aged ≥1 month; R/R CD33+ AML in adults and Please consult label for single-agent dosing and dosing in R/R AML. pediatric pts aged 2 y Phase 3 SIERRA study CD45 Adults aged ≥55 y with active R/R AML, adequate organ Dosimetry directed (SIERRA study) Iomab-B3 function, and related/unrelated matched donor (BC8 mAb linked to radioisotope iodine-131) Acute Lymphoblastic Leukemia EU EMA approved: Adults with R/R CD22+ B-cell ALL; adults Cycle 1 dose: 0.8 mg/m2 on d 1; 0.5 mg/m2 on days 8 and 15 for 21 d 2 Inotuzumab with Ph+ R/R B-cell ALL who failed treatment with at least one TKI CD22 Patients in CR/CRi: 0.5 mg/m on days 1, 8, and 15 for 28 d ozogamicin4,5 US FDA approved: Adults with R/R CD22+ B-cell ALL Patients not in CR/CRi: Use cycle 1 dose for 28 d EU Dose: By patient’s weight (≥45 kg = 9 mcg/d on d 1-7 and 28 mcg/d on EU EMA approved: Adults with B-cell ALL who are in d 8-28; <45 kg = 5 mcg/m2/d on -
Whither Radioimmunotherapy: to Be Or Not to Be? Damian J
Published OnlineFirst April 20, 2017; DOI: 10.1158/0008-5472.CAN-16-2523 Cancer Perspective Research Whither Radioimmunotherapy: To Be or Not To Be? Damian J. Green1,2 and Oliver W. Press1,2,3 Abstract Therapy of cancer with radiolabeled monoclonal antibodies employing multistep "pretargeting" methods, particularly those has produced impressive results in preclinical experiments and in utilizing bispecific antibodies, have greatly enhanced the thera- clinical trials conducted in radiosensitive malignancies, particu- peutic efficacy of radioimmunotherapy and diminished its toxi- larly B-cell lymphomas. Two "first-generation," directly radiola- cities. The dramatically improved therapeutic index of bispecific beled anti-CD20 antibodies, 131iodine-tositumomab and 90yttri- antibody pretargeting appears to be sufficiently compelling to um-ibritumomab tiuxetan, were FDA-approved more than a justify human clinical trials and reinvigorate enthusiasm for decade ago but have been little utilized because of a variety of radioimmunotherapy in the treatment of malignancies, particu- medical, financial, and logistic obstacles. Newer technologies larly lymphomas. Cancer Res; 77(9); 1–6. Ó2017 AACR. "To be, or not to be, that is the question: Whether 'tis nobler in the pembrolizumab (anti-PD-1), which are not directly cytotoxic mind to suffer the slings and arrows of outrageous fortune, or to take for cancer cells but "release the brakes" on the immune system, arms against a sea of troubles, And by opposing end them." Hamlet. allowing cytotoxic T cells to be more effective at recognizing –William Shakespeare. and killing cancer cells. Outstanding results have already been demonstrated with checkpoint inhibiting antibodies even in far Introduction advanced refractory solid tumors including melanoma, lung cancer, Hodgkin lymphoma and are under study for a multi- Impact of monoclonal antibodies on the field of clinical tude of other malignancies (4–6). -
Chemotherapeutic Treatment of Acute Myeloid Leukemia
Clinical Trial Outcomes Mahdi, Mahdi & Knapper Chemotherapeutic treatment of acute myeloid leukemia 5 Clinical Trial Outcomes Chemotherapeutic treatment of acute myeloid leukemia: incorporating the results of recent clinical trials Clin. Invest. (Lond.) Better outcomes for patients with acute myeloid leukemia over the last 30 years have Ali J Mahdi*,1, Eamon J been largely achieved by improvements in supportive care measures rather than Mahdi1 & Steven Knapper1 therapeutic advances. The combination of daunorubicin and cytarabine has remained 1Cardiff University School of Medicine, Hematology Department, Heath Park, the standard of care for patients undergoing intensive induction–consolidation Cardiff CF14 4XN, UK treatment. In less fit older patients, low-dose cytarabine is the equivalent, although *Author for correspondence: the hypomethylating agent azacitidine may be challenging current practice. [email protected] Enhanced understanding of disease pathogenesis and therapy resistance has enabled the entry of novel chemotherapeutic and nonchemotherapeutic agents into clinical development with varied levels of activity. This article examines the evidence behind established chemotherapy practices for intensive and nonintensive acute myeloid leukemia treatments with an emphasis on emerging clinical trial data from novel chemotherapeutic and nonchemotherapeutic agents. Keywords: acute myeloid leukemia • aminopeptidase inhibitors • farnesyl transferase inhibitors • FLT3 inhibitors • gemtuzumab ozogamicin • histone deacytylase inhibitors • hypomethylating • Polo-like kinase 1 inhibitors Methodology AML cases [7]. Older patients over the age of 10.4155/CLI.14.112 An electronic database search (EMBASE, 60 years thus represent an important popula- MEDLINE and PubMed) was undertaken tion from both demographic and therapeutic to identify and review clinical studies in perspectives. Older patients frequently have acute myeloid leukemia (AML) undertaken multiple comorbidities, unfavorable cyto- between 1 January 2009 and 1 June 2014.